This document addresses therapeutic apheresis, a procedure by which blood is removed from the body, separated into components, manipulated and returned to the individual. There are multiple pheresis procedures that are performed. The therapeutic apheresis procedures addressed in this document utilize devices approved by the United States (U.S.) Food & Drug Administration (FDA) and include the following subcategories:

• plasmapheresis/plasma exchange,
• cytapheresis (specifically, erythrocytapheresis, leukocytapheresis, platelet apheresis, red blood cell (RBC) exchange and thrombocytapheresis),
• low-density lipid (LDL) apheresis,
• selective high-density lipid (HDL) delipidation and therapeutic apheresis, and
• immunoadsorption (IA).

Note: This document does not address the use of apheresis in the development of autologous cellular immunotherapy, or an ex vivo gene therapy (for example: Zynteglo^® [betibeglogene autotemcel] or Skysona^® [elivaldogene autotemcel]). For criteria related to autologous cellular immunotherapy, refer to applicable guidelines used by the plan. For criteria related to pheresis when conducted as part of the development of an ex vivo gene therapy for the treatment of a genetic disease, see TRANS.00029 Hematopoietic Stem Cell Transplantation for Genetic Diseases and Aplastic Anemias.

Clinical Indications

Medically Necessary:

1. Plasmapheresis or plasma exchange is considered medically necessary for any of the following conditions listed in alphabetical order below:
   1. Acute inflammatory demyelinating polyradiculoneuropathy / Guillain-Barre syndrome
   2. Anti-glomerular basement membrane disease (Goodpasture's syndrome) when the individual is dialysis-independent or there is evidence of diffuse alveolar hemorrhage (DAH)
   3. Atypical hemolytic uremic syndrome (aHUS) with Factor H autoantibodies or complement gene mutation
   4. Autoimmune hemolytic uremic syndrome- severe cold agglutin disease when there has been an inadequate response to or failure of medical therapy
   5. Catastrophic antiphospholipid syndrome (CAPS)
   6. Chronic inflammatory demyelinating polyneuropathy when all of the following criteria are met:
      1. There is muscle weakness or sensory dysfunction caused by neuropathy in more than one limb; and
      2. Nerve conduction studies (NCS) or diagnostic criteria confirm evidence of a demyelinating neuropathy; and
      3. Other polyneuropathies such as IgM neuropathy, hereditary neuropathy, and diabetic neuropathy have been ruled out
   7. Cryoglobulinemia, symptomatic/severe, when there has been an inadequate response to or failure of medical therapy
   8. Hyperviscosity syndromes associated with monoclonal gammopathies (such as, multiple myeloma and Waldenström’s macroglobulinemia)
   9. Multiple myeloma cast nephropathy (acute renal failure secondary to multiple myeloma) when there has been an inadequate response to or failure of medical therapy
   10. Multiple sclerosis (MS)-acute attack/ relapse when there has been an inadequate response to or failure of medical therapy
   11. Myasthenia gravis, acute short-term treatment
   12. N-methyl D-aspartate receptor antibody encephalitis
   13. Neuromyelitis optica spectrum disorders, acute disease/relapse (excluding maintenance therapy) when there has been an inadequate response to or failure of medical therapy
   14. Paraproteinemic demyelinating neuropathies/ chronic acquired demyelinating polyneuropathies; associated with IgA, IgG or IgM monoclonal gammopathy of undetermined significance (MGUS) (excluding multiple myeloma, anti-myelin-associated glycoprotein (MAG) neuropathy or multifocal motor neuropathy (MMN))
   15. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) exacerbation when there has been an inadequate response to or failure of medical therapy
   16. Systemic lupus erythematosus - for individuals with severe or life-threatening symptoms when conventional therapy has failed to prevent clinical deterioration
   17. Thrombotic microangiopathy secondary to ticlopidine or malignancy
   18. Thrombotic Thrombocytopenic Purpura (TTP)
   19. Transplantation when any of the following are met:
       1. Hematopoietic stem cell transplant
          1. ABO incompatible; or
          2. Human leukocyte antigen (HLA) incompatibility with haplo-type transplant
       2. Solid organ transplantation for any of the following:
          1. Heart transplantation recipients who are in the operating room experiencing a hyper-acute rejection episode; or
          2. Liver transplantation from a live donor with ABO incompatibility; or
          3. Renal transplant recipients who are post-transplant and experiencing recurrent focal and segmental glomerulosclerosis (FGS) or experiencing a humoral or antibody mediated rejection; or
          4. Renal transplantation in highly sensitive kidney transplant candidates (high PRA protocols) to reduce the number of antibodies reactive against human lymphocyte antigens (HLA); or
          5. Renal transplantation, from a live donor with ABO incompatibility or positive cross-match, where a non-reactive live or cadaveric donor is unavailable; or
   20. Vasculitis anti-neutrophil cytoplasmic antibodies (ANCA) including granulomatosis with polyangiitis, microscopic polyangiitis and renal limited vasculitis, which associated with rapidly progressive glomerulonephritis and a creatinine level of 5.7 mg/dl or greater, or diffuse alveolar hemorrhage
   21. Voltage gated potassium channel antibodies when there has been an inadequate response to or failure of medical therapy
   22. Wilson’s disease – fulminant
2. Low-density lipid (LDL) apheresis or lipoprotein apheresis is considered medically necessary for individuals with any of the following:
   1. Homozygous familial hypercholesterolemia;
   2. Severe, refractory heterozygous familial hypercholesterolemia who have failed a 6-month trial of diet therapy and maximum tolerated combination drug therapy AND who meet either of the following FDA-approved indications:
      1. Functional hypercholesterolemic heterozygotes with low-density lipoprotein (LDL) that is greater than 300 mg/dL; or
      2. Functional hypercholesterolemic heterozygotes with LDL that is greater than 200 mg/dL and documented coronary artery disease
   3. Lipoprotein (a) hyperlipoproteinemia when there has been an inadequate response to or failure of medical therapy
3. Cytapheresis:
   1. Erythrocytapheresis (or phlebotomy) is considered medically necessary as a treatment for any of the following:
      1. Hereditary hemochromatosis
      2. Polycythemia vera
      3. Porphyra cutanea tarda
   2. Leukocytapheresis is considered medically necessary for symptomatic hyperleukocytosis
   3. Thrombocytapheresis is considered medically necessary for essential thrombocytosis (symptomatic, when the platelet count is greater than 1,000,000/mm³)
   4. Red blood cell exchange is considered medically necessary as treatment for any of the following:
      1. Babesiosis:
         1. Severe
         2. In the high-risk population
      2. Sickle cell disease, acute:
         1. Acute stroke
         2. Acute severe, chest syndrome
         3. Pregnancy
      3. Sickle cell disease, chronic exchange or non-acute:
         1. Stroke prophylaxis (primary or secondary)
4. Immunoadsorption is considered medically necessary for individuals with any of the following:
   1. Thrombotic Thrombocytopenic Purpura (TTP); or
   2. Acute inflammatory demyelinating polyradiculoneuropathy / Guillain-Barre syndrome
   3. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) when all of the following criteria are met:
      1. Muscle weakness or sensory dysfunction caused by neuropathy is present in more than one limb; and
      2. Evidence of a demyelinating neuropathy is confirmed by nerve conduction studies (NCS) or diagnostic criteria; and
      3. Other polyneuropathies (for example IgM neuropathy, hereditary neuropathy or diabetic neuropathy) have been ruled out
   4. Myasthenia gravis, acute short-term treatment
   5. N-methyl D-aspartate receptor antibody encephalitis
   6. Renal transplant recipients who are ABO compatible who are experiencing antibody mediated rejection (AMR) or require desensitization (living donor)
   7. Renal transplant recipients who are ABO incompatible and require desensitization (living donor)
   8. Renal transplant recipients who are post-transplant and experiencing recurrent focal segmental glomerulosclerosis (FSGS)

Not Medically Necessary:

1. Plasmapheresis or plasma exchange is considered not medically necessary when the criteria for plasmapheresis or plasma exchange above are not met and for all other indications.
2. Low-density lipid apheresis or lipoprotein apheresis is considered not medically necessary when the criteria for low-density lipid apheresis or lipoprotein apheresis above are not met and for all other indications.
3. Selective high-density lipid (HDL) delipidation and therapeutic apheresis is considered not medically necessary for all indications.
4. Cytapheresis is considered not medically necessary when the criteria for cytapheresis above are not met and for all indications.
5. Thrombocytapheresis is considered not medically necessary when the criteria for thrombocytopheresis above are not met and for all other indications.
6. Red blood cell exchange is considered not medically necessary when the criteria for red blood cell exchange above are not met and for all other indications.
7. Adsorptive cytapheresis is considered not medically necessary when the criteria for adsorptive cytapheresis above are not met and for all other indications.
8. Immunoadsorption pheresis is considered not medically necessary when the criteria for immunoadsorption pheresis above are not met and for all other indications.